A wide variety of biodegradable (also often designated as bioresorbable or biomedical) materials are known that are mostly based on aliphatic polyesters (Uhrich et al., Chem. Rev. 99, 3181-3198, 1999). The mechanical properties of current biodegradable materials are strongly related to their high molecular weights that are in general over 100 kDa, the presence of chemical cross-links, and the presence of crystalline domains in these polymers. Although the crystalline domains are beneficial for the initial high strength of the material, they do have a strong impact on the biodegradation process of the material as the biodegradation of crystalline domains is in general very slow and crystalline domains may cause immunological responses. Moreover, the need for high molecular weight polymers, in order to get the desired material properties, usually implies that high processing temperatures are required, and these are unfavourable as thermal degradation processes become more likely. Additionally, the crystalline domains may have a negative impact on the long term elastic behaviour of the material due to their tendency to induce fatigue characteristics.
The present invention relates to a supramolecular biodegradable polymer that comprises 4H-units that are capable of forming at least four H-bridges in a row, preferably with another 4H-unit, leading to physical interactions between different polymer chains. The physical interactions originate from multiple hydrogen bonding interactions (supramolecular interactions) between individual 4H-units or between a 4H-unit and another moiety capable of forming hydrogen bonds thereby forming self-complementary units, preferably comprising at least four hydrogen bonds in a row. Units capable of forming at least four hydrogen bonds in a row, i.e. quadruple hydrogen bonding units, are in this patent application abbreviated as “4H-units”. Sijbesma et al. (U.S. Pat. No. 6,320,018; Science 278, 1601-1604, 1997; both incorporated by reference) discloses 4H-units that are based on 2-ureido-4-pyrimidones. These 2-ureido-4-pyrimidones in their turn are derived from isocytosines.
A low molecular weight telechelic polycaprolactone (PCL) end-capped with 4H-units is disclosed in Dankers et al. (Polymeric Materials Sci. & Eng. 88, 52, 2003; Nature Materials 4, 5688, 2005 both incorporated by reference). It was found that films of this material were biocompatible based on the observed attachment of fibroblast cells to the films. The study on the biodegradation of this polymer showed the presence of crystallites, which is not favourable for bioresorption. Moreover, DSC-thermograms revealed the highly crystalline nature of the PCL backbone. The same PCL material and PCL materials comprising several 4H-units along the backbone are further characterized on their mechanical behaviour in Dankers et al. (Biomaterials 27, 5490, 2006; incorporated by reference). This study revealed that the highly crystalline telechelic PCL with 4H-units has a Young's modulus of about 130 MPa but breaks already after about 14% elongation. Whereas, the much less crystalline chain extended PCL-derivative with 4H-units has a lower Young's modulus of only about 3 MPa and an elongation of break of 576% (cf. Table 1 on page 5495). Both materials have only one melting point above 40° C. for the pristine non-annealed materials.
US 2009/00130172, incorporated by reference, discloses several biodegradable materials that comprise 4H-units mixed with bioactive molecules comprising a 4H-unit for biomedical applications such as coatings with controlled release of drugs. Among the materials disclosed are the materials as published by Dankers et al. mentioned above, as well as other biodegradable polyester derivatives comprising 4H-units, notable the telechelic PCL of Dankers et al. in Example 14, and the chain extended PCL and polyadipate-based polymers with isophorone diisocyanate (IPDI) in Examples 8, 12, 13, and 15. However, all these polyester based materials are characterized by poor mechanical behaviour, either not strong enough (modulus lower than 10 MPa) or not elastic enough (elongation below 50%).
Söntjens et al. (Macromolecules 41, 5703, 2008; incorporated by reference) disclose the above mentioned polyadipate-based polymers which are chain extended with 4H-units, as well as their analogues with 1,6-hexamethylene diisocyanate (HDI). These materials are said to be suitable for biomedical applications e.g. in medical devices and tissue engineering. However, the IPDI-analogue has no thermal transition in DSC above 40° C. whereas the HDI-analogue has only one melting point above 40° C. Additionally, the materials have only a limited strength, with Young's moduli of about 1 and about 8 MPa for the IPDI-analogue and HDI-analogue, respectively, and tensile strengths below 3 MPa.
US 2004/0087755, incorporated by reference, discloses polyurethane based polymers end-capped with 4H-units, alkyl diol chain extenders, and 4,4′-methylene bis(phenyl isocyanate) (MDI), which can be used as hot melt adhesive or TPU foam. These materials have limited tensile strengths ranging from 2 to 8 MPa (Table 2) or stresses at 100% elongation between 2 to 4 MPa (Table 6). Most importantly, the aromatic MDI in these polyurethane materials hamper their possible use as biodegradable biomedical materials, since MDI is known to result in degradation products that can comprise highly toxic aniline and derivatives thereof.
US 2012/116014, incorporated by reference, discloses a process for the preparation of a supramolecular polymer comprising 1-50 4H-units, in which a 4H building block according to the formula 4H-(L-Fi)r, wherein 4H represents a 4H-unit, L represents a divalent, trivalent, tetravalent or pentavalent linking group, Fi represents a reactive group, and r is 1-4, is reacted with a prepolymer comprising a complementary reactive group, wherein the reaction mixture comprising said 4H building block and said prepolymer comprises less than 10 wt. % of a non-reactive organic solvent, based on the total weight of the reaction mixture. Most preferably, r is 2 and L is a divalent C1-C20 alkylene, arylene, arylalkylene or alkylarylene group, which implies that the 4H building block is preferably represented by the formula 4H-(L-Fi)2. The 4H building block is preferably prepared from a precursor of an isocytosine or a melamine derivative and a diisocyanate, wherein the diisocyanate is most preferably isophorone diisocyanate (IPDI) or methylene dicyclohexane 4,4′-diisocyanate (HMDI). The supramolecular polymer according to US 2012/116014 is preferably used in coating and adhesive compositions. However, supramolecular polymers obtained according to this preferred process are too stiff (high Young's modulus) and have a low elasticity.
Hence there is a need in the art for supramolecular biodegradable materials for biomedical applications that have a high strength and/or a high elasticity. Furthermore, it is desired that they can easily be prepared and processed in a biomedically acceptable way.
It is therefore an object of the present invention to provide strong supramolecular biodegradable polymers as well as a process to prepare such polymers. The supramolecular biodegradable polymers according to the present invention have better material characteristics than those of the prior art without compromising the beneficial processing properties of supramolecular polymers. It is another object of the present invention to provide strong supramolecular biodegradable polymers used in biomedical implants and scaffolds for tissue engineering.